ACS Medicinal Chemistry Letters最新文献

Provided herein are novel 3-sulfamoyl benzoate ester and benzamide compounds as TEAD modulators, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

This highlight outlines the development of novel imidazo-pyrimidine compounds as potent inhibitors targeting oncogenic KRAS mutations, including G12D, G12V, and G12C. The disclosure includes details on synthetic methods, biological evaluation, metabolic stability, and pharmaceutical compositions.

The present invention details novel inhibitors of ubiquitin-specific protease 1 (USP1) and their pharmaceutically acceptable forms, compositions, and methods of use. These compounds demonstrate therapeutic potential for the treatment and prevention of USP1-related diseases, either as single agents or in combination with additional therapeutic agents.

Provided herein are novel 1,4-dihydro-2H-pyrano[3,4-c]quinoline compounds, pharmaceutical compositions, use of such compounds in treating bacterial infections, tuberculosis or leprosy, and processes for preparing such compounds.

SARS-CoV-2 and -CoV viruses are major human pathogens. Due to their zoonotic nature as well as emerging drug-resistant mutations, new antivirals are needed. The viral papain-like protease (PLpro) is a drug target. Targeting the mostly hydrophobic S1′ pocket of PLpro, we designed and synthesized 21 amide compounds, among which several highly potent PLpro inhibitors were identified with IC₅₀ values as low as 16 nM. Structure–activity relationship analysis showed that an electron-deficient pyridine-containing amide group can significantly enhance the activity. The X-ray structure of the PLpro-compound 15 complex revealed that the pyridine ring has favorable π-π and electrostatic interactions with the electron-rich indole group of Trp106. Compound 15 is inactive against human ubiquitin-specific protease 7 and noncytotoxic to mammalian cells, showing excellent selectivity. It can potently inhibit cellular replication of SARS-CoV-2 with an EC₅₀ of 96 nM. These results show that compound 15 represents a novel pharmaceutical lead for further drug development.

A series of pyrrolopyridine analogs is described as inhibitors of the YAP–TEAD, TAZ–TEAD protein–protein interaction. In recent years the Hippo pathway has become a target of interest for the treatment of disorders and diseases such as cancer. It has been established that in its “switched-on”-state the Hippo pathway involves a cascade of kinases in the cytoplasm which results in the phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (Transcription coactivator with PDZ binding motif). Activated YAP/TAZ binds to the transcriptional enhanced associate domain (TEAD) transcription factor family (TEAD1–4) that get activated and induce the expression of several genes, many of which mediate cell survival and proliferation. Therefore, inhibition of YAP, TAZ, TEAD, and YAP–TEAD or TAZ–TEAD protein–protein interaction appears to be a reasonable strategy to prevent and/or treat cancer associated with the dysfunction of the Hippo pathway.

The invention in this patent application relates to compounds having structures represented generally herein by formula 1. These compounds are modulators of alpha 4 beta 7 integrin and may provide useful treatment for several inflammatory conditions such as inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease.

Provided herein are novel tricyclic compounds as TLR7 agonists, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

The invention in this patent application relates to imidazopyridinyl derivatives represented herein generally by Formula 1. These compounds are inhibitors of TLR9, and may potentially be useful in treating, preventing, or slowing fibrotic diseases including nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), idiopathic pulmonary fibrosis (IPF), primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC).

KIF18A is an ATP-dependent, plus end-directed mitotic kinesin that facilitates chromosome alignment and spindle microtubule dynamics during mitosis. Certain cancer types may be particularly vulnerable to KIF18A inhibition, specifically cancer cells with high levels of chromosomal instability (CIN). As part of efforts to identify KIF18A inhibitors, silicon atom replacement was explored to improve ligand-KIF18A interactions and ADME parameters. This tactic resulted in the discovery of a series of silapiperidine-containing KIF18A inhibitors and culminated in the identification and characterization of ATX020. ATX020 is a potent KIF18A inhibitor with a high degree of kinesin selectivity, favorable in vitro and in vivo ADME properties, and robust efficacy in the OVCAR-3 cell-derived xenograft (CDX) model. A high-resolution crystal structure of the KIF18A–tubulin complex and an experimentally guided model of ATX020 bound to the complex are provided, supporting future structure-based drug design of KIF18A inhibitors.